PROJECT SUMMARY Wildfire occurrence, duration, and intensity have heightened in recent decades and continue to impact the health of millions of individuals worldwide. Smoke that is emitted from wildfires consists of a complex mixture of particulate matter and toxic gases. The chemical composition of wildfire smoke is dependent upon the type of biomass burn conditions and fuel type, which are heavily influenced by geographical region. The chemical mixtures within wildfire smoke that humans are exposed to can consequently cause variable health outcomes through potentially different biological mechanisms. Human exposure to wildfire smoke represents a growing concern in public health, and adequately characterizing health risks associated with biomass smoke across varying burn conditions and geographic areas is not possible with the data currently available. The variabilities in toxicological responses across wildfire smoke exposure conditions have yet to be fully established and evaluated in the context of chemical composition. The growing threat of wildfires necessitates the elucidation of individual and/or co-occurring components of wildfire smoke that act as the primary drivers of toxicity. To address this important research issue, we expand upon a foundational study that has previously characterized the chemical constituents in various biomass burn scenarios and evaluated, in part, toxicological responses to these exposures in the mouse lung. Here, we leverage this extensive database and banked samples to: 1. characterize in vivo transcriptomic responses and pathway alterations associated with biomass smoke in the mouse lung; 2. integrate chemical-toxicity profiles using computational approaches to prioritize chemicals that are likely driving toxicity responses; and 3. further evaluate chemical drivers of biomass smoke toxicity responses using in vitro approaches. This research will be carried out through a collaboration with laboratories at the University of North Carolina at Chapel Hill and the U.S. Environmental Protection Agency, allowing for a unique combination of expertise for studying the primary drivers of wildfire smoke-induced toxicity. This expertise includes skills in computational toxicology, exposure science, and molecular biology, coupled with experience studying adverse health effects and immune responses induced by exposure to air pollutants.